Ishida T, Kobayashi N, Tojo T, Ishida S, Yamamoto T, Inoue J
Department of Oncology, University of Tokyo, Japan.
J Immunol. 1995 Dec 15;155(12):5527-35.
Signals sent through CD40 play crucial roles in B cell differentiation, including blocking apoptosis of germinal center B cells. In this study, using a murine B cell WEHI-231 line that undergoes apoptosis by the cross-linking of surface Ag receptors (sIgM), we have demonstrated that CD40 signalings are linked to induction of the Bcl-xL, Cdk4, and Cdk6 proteins whose expression was significantly suppressed by the apoptotic signal through sIgM. Mutational analyses of CD40 revealed that the domain of human CD40 required for blocking apoptosis of WEHI-231 cells coincides with that required for Bcl-xL induction. Signals through sIgM arrest cells in the G1 phase of the cell cycle, which is followed by apoptosis. However, while constitutive expression of Bcl-XL leads to the inhibition of apoptosis. Nevertheless, Bcl-xL fails to induce S phase entry. By CD40 signalings, both Cdk4 and Cdk6 resume their normal expression levels, which are sufficient for passing the restriction point in G1 even in the presence of the apoptotic signals mediated by sIgM. These results suggest that cooperation of Bcl-xL, Cdk4, and Cdk6 induced by CD40 signaling plays a key role in CD40-mediated selective growth of B cells.
通过CD40发出的信号在B细胞分化中发挥关键作用，包括阻止生发中心B细胞的凋亡。在本研究中，我们使用了一种小鼠B细胞系WEHI-231，该细胞系通过表面抗原受体（sIgM）的交联而发生凋亡，我们证明CD40信号传导与Bcl-xL、Cdk4和Cdk6蛋白的诱导有关，这些蛋白的表达被通过sIgM的凋亡信号显著抑制。对CD40的突变分析表明，阻断WEHI-231细胞凋亡所需的人CD40结构域与诱导Bcl-xL所需的结构域一致。通过sIgM发出的信号使细胞停滞在细胞周期的G1期，随后发生凋亡。然而，虽然Bcl-XL的组成型表达导致凋亡的抑制。尽管如此，Bcl-xL未能诱导进入S期。通过CD40信号传导，Cdk4和Cdk6都恢复到正常表达水平，即使在存在由sIgM介导的凋亡信号的情况下，这些水平也足以通过G1期的限制点。这些结果表明，由CD40信号传导诱导的Bcl-xL、Cdk4和Cdk6的协同作用在CD40介导的B细胞选择性生长中起关键作用。
